Discovery of two types of adrenal cancer

Adrenocortical carcinoma (also known as adrenal cortex cancer or ACC), is a generally aggressive tumour, with a mean survival rate of less than five years for those affected. Apart from metastasis, it exposes the patients to manifestations such as high blood pressure, diabetes, decreased potassium level, infections, etc. There is, however, some patient-dependent variation in tumour development. The team led by Prof. Bertherat at the Cochin Institute (Inserm – CNRS – Paris Descartes University) and the Expert Centre for Rare Adrenal Cancers at Cochin Hospital (AP-HP) has just published a molecular classification for this cancer in the journal Nature Genetics. The researchers identify many molecular abnormalities in these cancers that have not been well known until now, and thus reveal a new classification for these tumours.

This work involved 130 adrenocortical carcinomas, bringing together an initial cohort of some fifty tumour samples collected in the national research network COMETE (COrtico et MEdullosurrénale, Tumeurs Endocrines; COrtical and MEdullary adrenal Endocrine Tumours) and a second cohort of approximately 80 samples, collected within the European research network ENSAT (European Network for the Study of Adrenal Tumors). The complete genomes of these tumours were analysed by a combination of several high throughput genomic techniques, i.e. complete sequencing; study of the expression levels of all genes (transcriptomics) and of micro-RNAs (miRNAs); study of genetic variants (SNPs) and of gene methylation levels (epigenetics).

This study revealed the existence of two molecular types of adrenocortical carcinomas, one showing a relatively favourable prognosis for patients following complete surgery, and another for which the prognosis is unfavourable.

These two molecular types correspond to two different diseases. The type associated with a poor prognosis is characterised by a higher level of mutations, including recurrent alterations in a small group of genes already known to be involved in adrenocortical carcinoma (CTNNB1,TP53, CDKN2A, RB1, MEN1), or new genes (ZNRF3, DAXX, TERT, and MED12). In this study, ZNFR3 is specifically identified as a new tumour suppressor gene.

Moreover, specific profiles that distinguish these two cancer groups are shown by each of the following molecular analyses: gene and miRNA expression profiles, and pattern of methylation abnormalities.

This work opens up new clinical opportunities in the short term, especially in terms of predicting tumour prognosis following surgery on the lesion, and the possibility of conducting clinical studies according to tumour type. In the longer term, the research team suggests that results will allow identification of therapeutic targets specific for each of the subgroups. It is a further step in the development of a specific personalised medicine for rare cancers.

The researchers also anticipate new applications for these discoveries, especially applications based on the newly identified tumour suppressor gene ZNFR3.

Finally, the authors of the study emphasise the power of genomic methods and the importance of national and international multidisciplinary and multi-centre research networks, especially in the area of rare tumours.

This project has been developed in partnership with the French National Cancer League for several years, under the Cartes d’Identité des Tumeurs (Tumour Identity Card) programme.